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Pharmacology of Metformin—Its Molecular Mechanisms Underlying Versatile Cellular Responses

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (30 December 2023) | Viewed by 10176

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Guest Editor
Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Interests: immunometabolism; oncometabolism; oncoimmunology; tumor microenvironment; redox; senescence
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Special Issue Information

Dear Colleagues,

In the seventeenth century, herbal medicine with Galega officinalis (containing a guanidine compound that was used later as a template for metformin) was originally applied to the treatments for infectious disease with fever, including malaria infection, influenza outbreak, and snake bites. In some of the influenza patients, lowering blood glucose was observed as a beneficial side effect.

Nowadays, diverse effects of metformin (Met) against diabetes, cardiovascular diseases, cancers, cognitive decline, and ageing are widely appreciated. Met activates and promotes the proliferation of tumor-infiltrating CD8T lymphocytes (CD8TILs) while stimulating macrophage polarization into the M1-like phenotype and decreasing T regulatory cells (Treg) in the tumor microenvironment. On the other hand, Met prevents SARS-CoV-2-induced-lung damage via downregulating cytokine storm response. Met reduces inflammation by promoting the polarization of M2-like macrophages, Treg, and CD8 memory T cells. Met also attenuates autoimmune diseases, graft-versus-host disease.

In spite of the accumulation of evidence for such beneficial effect of Met, the underlying mechanisms are not fully understood. The social demands for the dissection of the detailed mechanisms have become higher than ever. In view of such events, this Special Issue, entitled “Pharmacology of Metformin—Its Molecular Mechanisms Underlying Versatile Cellular Responses”, specifically covers, but is not limited to, molecular mechanisms for the blood-glucose-lowering effect, cancer prevention, immunity, and longevity. For example, molecular mechanisms underlying preventions of cardiovascular diseases and neurodegeneration are welcome. Please be advised that molecular mechanism analysis would be encouraged but mere phenomenological theory or details of phenomena are not subject of adoption.

Prof. Dr. Heiichiro Udono
Guest Editor

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Keywords

  • AMP-activated protein kinases(AMPK)
  • reactive oxygen species (ROS)
  • nuclear factor- erythroid 2-related factor 2(Nrf2)
  • redox, autophagy
  • mTOR
  • p62/sequestosome1
  • metabolism
  • mitochondria
  • geroprotective science

Published Papers (2 papers)

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Research

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15 pages, 6656 KiB  
Article
Metformin Attenuates the Inflammatory Response via the Regulation of Synovial M1 Macrophage in Osteoarthritis
by Meng Zheng, Yuanli Zhu, Kang Wei, Hongxu Pu, Renpeng Peng, Jun Xiao, Changyu Liu and Xuying Sun
Int. J. Mol. Sci. 2023, 24(6), 5355; https://doi.org/10.3390/ijms24065355 - 10 Mar 2023
Cited by 5 | Viewed by 1926
Abstract
Osteoarthritis (OA), the most common chronic inflammatory joint disease, is characterized by progressive cartilage degeneration, subchondral bone sclerosis, synovitis, and osteophyte formation. Metformin, a hypoglycemic agent used in the treatment of type 2 diabetes, has been evidenced to have anti-inflammatory properties to treat [...] Read more.
Osteoarthritis (OA), the most common chronic inflammatory joint disease, is characterized by progressive cartilage degeneration, subchondral bone sclerosis, synovitis, and osteophyte formation. Metformin, a hypoglycemic agent used in the treatment of type 2 diabetes, has been evidenced to have anti-inflammatory properties to treat OA. It hampers the M1 polarization of synovial sublining macrophages, which promotes synovitis and exacerbates OA, thus lessening cartilage loss. In this study, metformin prevented the pro-inflammatory cytokines secreted by M1 macrophages, suppressed the inflammatory response of chondrocytes cultured with conditional medium (CM) from M1 macrophages, and mitigated the migration of M1 macrophages induced by interleukin-1ß (IL-1ß)-treated chondrocytes in vitro. In the meantime, metformin reduced the invasion of M1 macrophages in synovial regions brought about by the destabilization of medial meniscus (DMM) surgery in mice, and alleviated cartilage degeneration. Mechanistically, metformin regulated PI3K/AKT and downstream pathways in M1 macrophages. Overall, we demonstrated the therapeutic potential of metformin targeting synovial M1 macrophages in OA. Full article
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Review

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17 pages, 1154 KiB  
Review
Metformin and Its Immune-Mediated Effects in Various Diseases
by Ichiro Nojima and Jun Wada
Int. J. Mol. Sci. 2023, 24(1), 755; https://doi.org/10.3390/ijms24010755 - 1 Jan 2023
Cited by 12 | Viewed by 6215
Abstract
Metformin has been a long-standing prescribed drug for treatment of type 2 diabetes (T2D) and its beneficial effects on virus infection, autoimmune diseases, aging and cancers are also recognized. Metformin modulates the differentiation and activation of various immune-mediated cells such as CD4+ and [...] Read more.
Metformin has been a long-standing prescribed drug for treatment of type 2 diabetes (T2D) and its beneficial effects on virus infection, autoimmune diseases, aging and cancers are also recognized. Metformin modulates the differentiation and activation of various immune-mediated cells such as CD4+ and CD+8 T cells. The activation of adenosine 5′-monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) pathway may be involved in this process. Recent studies using Extracellular Flux Analyzer demonstrated that metformin alters the activities of glycolysis, oxidative phosphorylation (OXPHOS), lipid oxidation, and glutaminolysis, which tightly link to the modulation of cytokine production in CD4+ and CD+8 T cells in various disease states, such as virus infection, autoimmune diseases, aging and cancers. Full article
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